Microfluidic devices have been created that allow for the study of interactions within biological systems. More specifically, microfluidic devices exist that allow for the study of interactions between two channels, such as two fluid channels, separated by a membrane, such as a semi-permeable membrane. The membrane allows for cell migration, diffusion of soluble factors, etc. that are found in biological systems mimicked by the microfluidic devices. Such microfluidic devices have been created to study specific aspects of, for example, the human body, focusing on specific organs and/or tissues within the human body. These microfluidic devices are generally flat or planar, and the corresponding channel(s) and membrane(s) within these microfluidic devices also are generally flat or planar. The devices can be flat or planar because they are an approximation of small, flat organ sections, although the organ as a whole may be flat or curved. The generally flat or planar approximation of the microfluidic devices is possible because, for example, an intestine wall is effectively flat relative to a cell or soluble factor given the relative size difference; much like Earth is effectively flat relative to its inhabitants.
However, many biological systems can consist of concentric tissues or tubes, or tubes within tubes, that interact with one another through various mechanisms, including diffusion of soluble factors, cell migration, vascularization, and cell-to-cell contact at one or more interfaces. The concentric tissues or tubes found within biological systems consequently exhibit radial gradients of various components found within, such as radial gradients of cells or soluble factors. These radial gradients can be more important at smaller length scales. The conventional microfluidic devices that are generally flat or planar do not allow for the generation of these radial gradients, and also do not provide for radial interactions. The generally flat or planar microfluidic devices also may not allow for tissue formation, such as vascularization, between the two channels. The generally flat or planar microfluidic devices also may not easily accommodate more than two channels, or may not allow for the loading of fluid and/or material into the devices. These drawbacks limit or prevent the study of complex processes that normally occur between three or more tissue layers, such as the processes involved in bone marrow interactions with bone and vasculature, cancer cells with vascular and lymphatic endothelium, and the like.
Another possible drawback with conventional microfluidic devices that are generally flat or planar is that imaging of the processes within the devices must occur through the devices themselves, such as through top portions or bottom portions of the devices. In addition, or in the alternative, the generally flat or planar nature of the conventional microfluidic devices results in stacking of the two channels. The stacked channels result in imaging of one channel also capturing the other channel. In other words, the top and bottom channels are imaged at once, which inhibits or prevents detailed, real-time analysis of the interfacial processes from a tissue cross-section vantage point. For example, to observe the interface of tissues in conventional microfluidic devices, confocal microscopy can be used to look at the relationship of cells at the interface because of the optical overlap of top and bottom channels. However, confocal microscopy requires staining and the microfluidic devices being fixed, which prevents multiple time point analyses for the same microfluidic device.
Another possible drawback with conventional microfluidic devices that are generally flat or planar is that the devices are limited to having channels and not, for example, wells. The channels require a steady stream of fluid to pass into and out of the devices, rather than having fluid remain within the devices, such as in a batch process within a well. Thus, batch process sampling within the device is not possible.
The below-described devices, methods, and systems solve many of the problems associated with the current art by providing concentric (or eccentric) channels, rings, and wells within a microfluidic device that allow for the generation and analysis of radial gradients. The below-described devices, methods, and systems also provide access to one or more of the channels, rings, and wells for imaging the processes within the devices, specific to the channels, rings, and wells, or interfaces therebetween. The open design of the devices and systems also provide for simultaneous sampling of one or more of the channels, rings, and wells for further analysis of the processes occurring therein.